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Exercise stress testing is routinely performed to evaluate suspected coronary artery disease in older adults. However, the available data to predict and compare relative exercise capacity in the general population were developed using predominantly younger, healthy cohorts with few or no women. This study aimed to describe the exercise capacity of patients older than 75 years who underwent a clinically indicated Bruce protocol exercise stress test. This was a retrospective, cross-sectional study of 2,041 consecutive patients older than 75 years who performed a Bruce protocol exercise stress echocardiogram that was terminated because of maximal effort without ischemia at Columbia University Medical Center between April 10, 2009, and July 30, 2020. The analytic sample included 2,041 exercise stress tests in 786 women (median [interquartile range] age 79 [77 to 81] years) and 1,255 men (median [interquartile range] age 79 [77 to 82] years). Cardiovascular risk factors and clinical coronary disease were common and more prevalent in men than women. The median exercise time for men aged 76 to 80 years was 7:22 (minutes:seconds) and for women was 6:00 and significantly decreased in both genders as age increased (p

Introduction: Euphorbia tirucalli, commonly known as pencil cactus, is a member of the Euphorbiaceae family that produces a milky, white latex substance that can cause local irritation if ingested ...

Background Acne affects more than 80% of adolescents and young adults, who most often develop acne scars. Supporting data on the effect of acne scars on patient’s health-related quality of life (HRQOL) are limited. Objective The aim was to determine how the severity of acne scars impacts the HRQOL of afflicted individuals. Methods In this population-based cross-sectional study, 723 adults with facial acne scars but without active acne lesions self-completed the Self-assessment of Clinical Acne-Related Scars (SCARS) questionnaire formulated to investigate degree of acne scarring. The Facial Acne Scar Quality of Life (FASQoL), Dermatology Life Quality Index (DLQI), and Dysmorphic Concern Questionnaire (DCQ) were completed to assess the attitude of these patients toward their scars and the impact of scarring on their HRQOL. Results The mean (standard error) DLQI score for facial acne scars was 6.26 (0.22). Acne scars were considered a ‘very large’ or ‘extremely large’ concern by 19.3% of participants with mild scars as compared to 20.1% and 34.0% of participants with moderate and severe/very severe scars, respectively (P = 0.003). Higher FASQoL scores were associated with increased severity of scarring (P = 0.001). In total, 16.9% of participants had clinical features of dysmorphia (i.e., DCQ > 13). DCQ scores were significantly higher among participants with more severe scarring (mean DCQ score of 8.04 [0.28], 8.40 [0.18], and 10.13 [0.08] among participants with mild, moderate, and severe/very severe acne scars, respectively; P = 0.001). Most commonly reported signs of emotional distress were self-consciousness (68.0%) and worry about scars not going away (74.8%). Conclusions This study highlights the significant psychosocial impact of atrophic acne scars in the form of embarrassment and self-consciousness. Individuals with mild scars also expressed significant impact on quality of life that increased with aggravation of scar severity. Patient-reported outcomes provide an insight into the physical, functional, and psychological impact of acne scarring from the patient’s perspective. Supplementary Information The online version contains supplementary material available at 10.1007/s40257-021-00628-1.

Background Truncal acne is common and burdensome for patients; however, there is paucity of evidence and guidance for the management of truncal acne. Currently, clinical practice guidelines provide very little guidance on the assessment or management of truncal acne. Objectives To identify unmet needs in truncal acne and make recommendations to address clinical and management gaps using an international consensus. Methods The Personalising Acne: Consensus of Experts panel consisted of 13 dermatologists, who used a modified Delphi approach to reach a consensus on statements related to clinically relevant aspects of truncal acne evaluation and management. A consensus was defined as ≥75% of the panelists voting "agree" or "strongly agree." The voting was electronic and blinded. Results The panel identified gaps and made recommendations related to truncal acne identification, assessment, and grading; the evaluation of the impact on patients; and treatment goals and factors to be considered for its management. Limitations The recommendations are based on expert opinion, in the absence of high-quality evidence. Conclusions We highlighted addressing not just facial acne but also truncal acne during patient consultations. The recommendations made herein may help facilitate the care of patients who present with truncal acne, with or without facial acne.

Background: Leishmaniasis is a globally important yet neglected parasitic disease transmitted by phlebotomine sand flies. With new candidate vaccines in or near the clinic, a controlled human challenge model (CHIM) using natural sand fly challenge would provide a method for early evaluation of prophylactic efficacy. Methods: We evaluated the biting frequency and adverse effects resulting from exposure of human volunteers to bites of either Phlebotomus papatasi or P. duboscqi, two natural vectors of Leishmania major. 12 healthy participants were recruited (mean age 40.2 ± 11.8 years) with no history of significant travel to regions where L. major-transmitting sand flies are prevalent. Participants were assigned to either vector by 1:1 allocation and exposed to five female sand flies for 30 minutes in a custom biting chamber. Bite frequency was recorded to confirm a bloodmeal was taken. Participant responses and safety outcomes were monitored using a visual analogue scale (VAS), clinical examination, and blood biochemistry. Focus groups were subsequently conducted to explore participant acceptability. Results: All participants had at least one successful sand fly bite with none reporting any serious adverse events, with median VAS scores of 0-1/10 out to day 21 post-sand fly bite. Corresponding assessment of sand flies confirmed that for each participant at least 1/5 sand flies had successfully taken a bloodmeal (overall mean 3.67±1.03 bites per participant). There was no significant difference between P. papatasi and P. duboscqi in the number of bites resulting from 5 sand flies applied to human participants (3.3±0.81 vs 3.00±1.27 bites per participant; p=0.56). In the two focus groups (n=5 per group), themes relating to positive participant-reported experiences of being bitten and the overall study, were identified. Conclusions: These results validate a protocol for achieving successful sand fly bites in humans that is safe, well-tolerated and acceptable for participants. Clinicaltrials.gov registration: NCT03999970 (27/06/2019)

Our objective was to identify concerns, burden of disease, education gaps, and expectations of acne/acne scarring respondents and investigate acne/acne scarring related burden. Also, to consider perception of acne/acne scarring and additional education needs through responses from the general population.One online survey from 1000 respondents aged 14ndash;26 years old who currently had moderate to severe acne and/or acne scarring (AcnePop) and one from 2000 nationally representative USA respondents agedge;14 years old [general population (GenPop)].Among the AcnePop, 26% had never consulted a healthcare professional and 36% never received a prescription for acne/acne scarring. Of those who had seen a medical professional, 72% consulted a dermatologist, 45% a primary care physician, and 23% a therapist/psychiatrist. The vast majority (94%) were dissatisfied with information they received from the healthcare provider. Topics they desired more information on included available treatment options (46%), how different skin types are affected by acne (44%), acne triggers (44%), and their acne severity (43%). Of GenPop (n=781) who had given unsolicited advice to people with acne, the most common suggestions were to see a doctor (47%), change their hygiene habits (39%), or change their diet (37%).AcnePop are often dissatisfied with the information they receive from healthcare providers and more comprehensive information should be provided to help them understand their condition and available treatment options. J Drugs Dermatol. 2021;20(6):600-606. doi:10.36849/JDD.5920.

Background A controlled human infection model (CHIM) involves deliberate exposure of volunteers to pathogens to assess their response to new therapies at an early stage of development. We show here how we used public involvement to help shape the design of a CHIM to support future testing of candidate vaccines for the neglected tropical disease cutaneous leishmaniasis, a disease transmitted by the bite of infected sand flies in tropical regions. Methods We undertook a public involvement (PI) consultation exercise to inform development of a study to test the safety and effectiveness of a sand fly biting protocol using uninfected sand flies (FLYBITE: ClinicalTrials.gov ID NCT03999970) and a CHIM using Leishmania major-infected sand flies (LEISH_Challenge: ClinicalTrials.gov ID NCT04512742), both taking place in York, UK. We involved 10 members of the public including a patient research ambassador and a previous CHIM volunteer. The session took place at The University of York, UK and examined draft study volunteer-facing material and included the CHIM study design, potential adverse events and therapeutic interventions at study endpoints. A discussion of the scientific, ethical, humanitarian and economic basis for the project was presented to the participants to provoke discourse. An inductive, thematic analysis was used to identify the participants’ key concerns. Results Themes were identified relating to i) quality of volunteer-facing written information, ii) improving study design, and iii) factors to motivate involvement in the research. Group participants responded positively to the overall study aims. Initial concerns were expressed about potential risks of study involvement, but further explanation of the science and mitigations of risk secured participant support. Participants provided advice and identified improved terminology to inform the volunteer-facing material. Lastly, treatment options were discussed, and excision of any cutaneous lesion was favoured over alternatives as a treatment. Conclusion The consultation exercise provided invaluable information which led to improved study design and enhanced clarity in the volunteer-facing material. The session also reinforced the need to maintain public trust in scientific rigour prior to initiation of any study. The investigators hope that this description strengthens understanding of PI in clinical research, and encourages its use within other studies. Supplementary Information The online version contains supplementary material available at 10.1186/s40900-021-00277-y., Plain English summary Our research team is designing a type of research study known as a controlled human infection model (CHIM). In CHIM studies, volunteers are exposed to infections on purpose and then studied to help understand diseases. Similar experiments, where humans are infected deliberately, have been used for hundreds of years to help test treatments. CHIM studies have already been used more recently to help test vaccines for diseases such as malaria. The disease leishmaniasis, a disease affecting millions each year, is spread by the bite of an infected sand fly in tropical countries. There are currently no vaccines for leishmaniasis that are available for use in humans. It is thought that by using CHIM studies, new vaccines might be tested and then approved more quickly. Scientific researchers have had many discussions about how useful CHIM studies are, especially in terms of the science behind them, the safety of volunteers and the ethics of these studies. Researchers also understand how important it is to involve the public in designing and carrying out research, especially studies involving humans, to get an independent point-of-view. We have therefore involved the public, in some parts of designing this research, in a group discussion. We also included a person who has already taken part in a different CHIM study. These discussions have had an important effect and have changed how we plan to carry out our future research studies. We also hope that this description will encourage other researchers to include the public when planning future research. Supplementary Information The online version contains supplementary material available at 10.1186/s40900-021-00277-y.

BACKGROUNDIncreasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19.METHODSWe conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60.RESULTSOverall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI −0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined ≥70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19.CONCLUSIONSAlthough not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged ≥70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged ≥70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).

Background\udAcne is very common and can have a substantial impact on wellbeing. Guidelines suggest first-line management with topical treatments, but there is little evidence regarding which treatments are most effective.\ud\udObjectives\udTo identify the most effective and best tolerated topical treatments for acne using network meta-analysis.\ud\udMethods\udCENTRAL, MEDLINE, Embase and World Health Organization Trials Registry were searched from inception to June 2020 for randomized trials that included participants with mild/moderate acne. Primary outcomes were self-reported improvement in acne, and trial withdrawal. Secondary outcomes included change in lesion counts, Investigator’s Global Assessment, change in quality of life and total number of adverse events. Network meta-analysis was undertaken using a frequentist approach. Risk of bias was assessed using the Cochrane Risk of Bias Tool and confidence in evidence was assessed using CINeMA.\ud\udResults\udA total of 81 papers were included, reporting 40 trials with a total of 18 089 participants. Patient Global Assessment of Improvement was reported in 11 trials. Based on the pooled network estimates, compared with vehicle, benzoyl peroxide (BPO) was effective (35% vs. 26%) for improving self-reported acne. The combinations of BPO with adapalene (54% vs. 35%) or with clindamycin (49% vs. 35%) were ranked more effective than BPO alone. The withdrawal of participants from the trial was reported in 35 trials. The number of patients withdrawing owing to adverse events was low for all treatments. Rates of withdrawal were slightly higher for BPO with adapalene (2·5%) or clindamycin (2·7%) than BPO (1·6%) or adapalene alone (1·0%). Overall confidence in the evidence was low.\ud\udConclusions\udAdapalene in combination with BPO may be the most effective treatment for acne but with a slightly higher incidence of withdrawal than monotherapy. Inconsistent reporting of trial results precluded firmer conclusions.

Background Acne confers an increased risk of physical, psychiatric, and psychosocial sequelae, potentially affecting multiple dimensions of health-related quality of life (HRQoL). Morbidity associated with truncal acne is poorly understood. Objective To determine how severity and location of acne lesions impact the HRQoL of those who suffer from it. Methods A total of 694 subjects with combined facial and truncal acne (F+T) and 615 with facial acne only (F) participated in an online, international survey. Participants self-graded the severity of their acne at different anatomical locations and completed the dermatology life quality index (DLQI). Results The F+T participants were twice as likely to report "very large" to "extremely large" impact on HRQoL (ie, DLQI > 10 and children's DLQI [CDLQI] > 12) as compared with the F participants (DLQI: odds ratio [OR] 1.61 [95% confidence interval {CI} 1.02-2.54]; CDLQI: OR 1.86 [95% CI 1.10-3.14]). The impact of acne on HRQoL increased with increasing acne severity on the face (DLQI and CDLQI P values = .001 and .017, respectively), chest (P = .003; P = .008), and back (P = .001; P = .028). Limitations Temporal evaluation of acne impact was not estimated. Conclusions Facial and truncal acne was associated with a greater impact on HRQoL than facial acne alone. Increasing severity of truncal acne increases the adverse impact on HRQoL irrespective of the severity of facial acne.

ObjectivesTo examine the acceptability and validity of two patient-reported outcome measures (PROMs) for adult acne, comparing them to the validated Acne-specific Quality of Life (Acne-QoL) measure.DesignMixed-methods validation study.SettingParticipants were recruited by (1) mail-out through primary care if they had ever consulted for acne and received a prescription for acne treatment within the last 6 months, (2) opportunistically in secondary care and (3) poster advertisement in community venues.Participants221 (204 quantitative and 17 qualitative) participants with acne, aged 18–50 years.Outcome measuresQuantitative sub-study participants completed Acne-QoL, Skindex-16 and Comprehensive Acne Quality of Life Scale (CompAQ) at baseline, 24 hours and 6 weeks. Qualitative sub-study participants took part in cognitive think-aloud interviews, while completing the same measures. Transcribed audio recordings were analysed using inductive thematic analysis.ResultsQuantitative analyses suggested high internal consistency (Cronbach’s alpha 0.74–0.96) and reliability (intraclass correlation coefficient values 0.88–0.97) for both questionnaires. Both scales showed floor effects on some subdomains. Skindex-16 and CompAQ showed good evidence of construct validity when compared with Acne-QoL with Spearman’s correlation coefficients 0.54–0.81, and good repeatability over 24 hours.Qualitative data uncovered wide-ranging views regarding usability and acceptability. Interviewees held strong but differing views about layout, question/response wording, redundant/similar questions and guidance notes. Similarly, interviewees differed in perceptions of acceptability of the different scales, particularly on relatability of questions and emotive reactions to scales.ConclusionsAll PROMs performed well in statistical analyses. No PROM showed superior usability and acceptability in the qualitative study. Any PROM should be acceptable for further research in adult acne but researchers should consider the different domains and whether they will measure only facial or facial and trunk acne before making a selection. A new PROM or further evaluation of novel PROMs may be beneficial.

Clinical trial results should address outcomes that matter to patients and their clinicians. The legacy of inadequate external validity of outcome measures in clinical trials extends across all fields of medicine and is a waste of resources. It also represents a lost opportunity to generalize findings to facilitate comparative effectiveness research. The minimal set of outcome measures that should be included in all clinical trials of a target condition is termed a core outcome set (COS). This should comprise all relevant outcome domains (i.e. what to measure) and their respective measures (how to measure). The methodology for COS development and dissemination has been previously extensively detailed and is increasingly being applied to various dermatological conditions including acne, atopic dermatitis, psoriasis and hidradenitis suppurativa.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6–180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42–120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway., Graphical abstract, Post-kala-azar dermal leishmaniasis (PKDL) is a chronic parasitic disease with limited treatment options. Here, Musa and colleagues report on a phase IIa therapeutic trial of the adenoviral-vectored leishmaniasis vaccine ChAd63-KH. Single-dose vaccination with ChAd63-KH was safe and induced innate and T cell responses in Sudanese patients with PKDL.

This study compared titanium (Ti), palladium (Pd), platinum (Pt), and gold (Au) ion release following induced accelerated tribocorrosion from three Au alloy abutment groups coupled with Ti implants over time; investigated contacting surface structural changes; and explored the effect of Au plating. Three abutment groups, G (n = 8, GoldAdapt, Nobel Biocare), N (n = 8, cast UCLA, Biomet3i), and P (n = 8, cast UCLA, Biomet3i, Au plated), coupled with implants (Nobel Biocare), immersed in 1% lactic acid, were cyclically loaded. Ions released (ppb) at T1, T2, and T3, simulating 3, 5, and 12 months of function, respectively, were quantified by inductively coupled plasma mass spectrometry (ICP-MS) and compared. Surface degradation and fretted particle composition after T3 were evaluated with scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM/EDX). ICP-MS data were nonparametric, expressed as medians and interquartile ranges. SEM/EDX showed pitting, crevice corrosion, and fretted particles on the components. Released ion concentrations in all groups across time significantly decreased for Pd (P < .001, median range: 1.70–0.09), Pt (P = .021, 0.55–0.00), and Au (P < .001, 1.01–0.00) and increased for Ti (P = .018, 2.49–5.84). Total Ti release was greater than other ions combined for G (P = .012, 9.86–2.30) and N (P < .001, 13.59–5.70) but not for P (P = .141, 8.21–3.53). Total Ti release did not differ between groups (P = .36) but was less variable across group P. On average, total ion release was 13.77 ppb (interquartile range 8.91–26.03 ppb) across the 12-month simulation. Tribocorrosion of Ti implants coupled with Au abutments in a simulated environment was evidenced by fretted particles, pitting, and crevice corrosion of the coupling surfaces and release of ions. More Ti was released compared with Pd, Pt, and Au and continued to increase with time. Abutment composition influenced ion release. Au-plated abutments appeared to subdue variation in and minimize high-concentration spikes of titanium.

Post kala azar dermal leishmaniasis (PKDL) is a chronic, stigmatising skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a Phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (NCT02894008) was an open label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration 30 months; range 6 -180 months). Patients received a single intramuscular vaccination of 1×1010 viral particles (v.p.; adults only) or 7.5×1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow up. AmBisome® was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole blood transcriptomics and ELISpot. 7 patients (30.4%) monitored to study completion showed >90% clinical improvement and 6 (25%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomised controlled trial to determine whether these clinical responses were vaccine related and whether ChAd63-KH vaccine has clinical utility is underway.

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIM) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical isolate of Leishmania major. Two fresh isolates of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one (L. major_MRC-02) to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

Background Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation for end-stage interstitial lung disease (ILD) and pulmonary hypertension (PH) has varying results based on ECMO configuration. We compare our experience using venovenous (VV) and venoarterial (VA) ECMO bridge to transplantation for ILD with PH on survival to successful transplantation. Methods A single-center retrospective review was done of patients with ILD and secondary PH who were placed on either VV or VA ECMO as bridge to transplantation from 2010 to 2016. Comparisons for factors associated with survival to transplantation between VV and VA ECMO strategies were made using Cox proportional hazards model. Subgroup analysis included comparisons of VV ECMO patients who remained on VV or were converted to VA ECMO. Results A total of 50 patients with ILD and PH were treated initially with either VV (n = 19) or VA (n = 31) ECMO as bridge to lung transplantation. Initial VA ECMO had a significantly higher survival to transplantation compared with initial VV ECMO (p = 0.03). Cox proportional hazards modeling showed a 59% reduction in risk of death for VA compared with VV ECMO (hazard reduction 0.41, 95% confidence interval: 0.18 to 0.92, p = 0.03). Patients converted from VV to VA ECMO had significantly longer survival awaiting transplant than patients who remained on VV ECMO (p = 0.03). Ambulation on ECMO before transplantation was associated with an 80% reduction in the risk of death (hazard reduction 0.20, 95% confidence interval: 0.08 to 0.48, p Conclusions Venoarterial ECMO upper body configuration for patients with end stage ILD and PH significantly improves overall survival to transplantation.

Objectives To report the clinical outcomes for patients with implants treated for peri-implantitis who subsequently received supportive care (supportive peri-implant/periodontal therapy) for at least 3 years. Material and methods A systematic search of multiple electronic databases, grey literature and hand searching, without language restriction, to identify studies including ≥10 patients was constructed. Data and risk of bias were explored qualitatively. Estimated cumulative survival at the implant- and patient-level was pooled with random-effects meta-analysis and explored for publication bias (funnel plot) at different time intervals. Results The search identified 5,761 studies. Of 83 records selected during screening, 65 were excluded through independent review (kappa = 0.94), with 18 retained for qualitative and 13 of those for quantitative assessments. On average, studies included 26 patients (median, IQR 21-32), with 36 implants (median, IQR 26-45). Study designs (case definitions of peri-implantitis, peri-implantitis treatment, supportive care) and population characteristics (patient, implant and prosthesis characteristics) varied markedly. Data extraction was affected by reduced reporting quality, but over 75% of studies had low risk of bias. Implant survival was 81.73%-100% at 3 years (seven studies), 74.09%-100% at 4 years (three studies), 76.03%-100% at 5 years (four studies) and 69.63%-98.72% at 7 years (two studies). Success and recurrence definitions were reported in five and two studies respectively, were heterogeneous, and those outcomes were unable to be explored quantitatively. Conclusion Therapy of peri-implantitis followed by regular supportive care resulted in high patient- and implant-level survival in the medium to long term. Favourable results were reported, with clinical improvements and stable peri-implant bone levels in the majority of patients.

Evaluate intra- and inter-examiner agreement of radiographic marginal bone level (MBL) assessment around Brånemark single implants; and whether agreement related to radiograph brightness, discrimination level (accuracy), participant demographics or implant characteristics.Seventy-four participants assessed MBLs of 100 digital radiographs twice with normal brightness, and twice with increased brightness. Intra-examiner agreement with and without increased brightness to the same thread, and within one thread; and inter-examiner agreement as compared with the group (defined by the mode) for the first assessments with and without increased brightness, to the same thread, and within one thread were calculated with Cohen's Kappa. Relationships between agreement, thread discrimination level (accuracy), brightness, participant and implant characteristics were explored.When assessing 100 "Normal" radiographs twice, a participant on average assessed 24% differently to themselves (poor intra-examiner agreement, median Kappa 0.58, range 0.21-0.82); and 28% differently to other participants (poor inter-examiner agreement, median Kappa 0.53, range 0.05-0.80). Agreement within examiners improved when radiographs were "Bright" (median Kappa 0.58 vs. 0.62, p 0.001, accuracy to same thread; median Kappa 0.94 vs. 0.96, p 0.001, accuracy within one thread). Agreement between examiners was neither better nor worse when radiographs were "Bright" (median Kappa 0.53 vs. 0.55, p = 0.64, accuracy to same thread; median Kappa 0.93 vs. 0.93, p = 0.23, accuracy within one thread). Intra- and inter-examiner agreements were lower when accuracy to the same thread was required (p 0.001, p 0.001). Neither intra- nor inter-examiner agreement related to age, time since graduation, specialty, viewing device, implant experience, external hex familiarity, periimplantitis treatment experience, implant location or width (p-values 0.05-0.999). Intra-examiner agreement increased across dental assistants (n = 11), general dentists (n = 16) and specialists (n = 47) ("Bright" assessments, p = 0.045, median Kappa's 0.55, 0.60, 0.65 respectively); and for females (n = 8, males = 58) ("Normal" assessments, p = 0.019, median 0.68 vs. 0.55), but female numbers were low.Agreement within and between examiners when assessing MBLs was poor. Disagreement occurred around 25% of the time, potentially affecting consistent disease assessments. No participant or implant characteristic clearly affected agreement. Brighter radiographs improved intra-examiner agreement. Overall, perceived MBL changes below 1 mm are likely due to human, not biological variation.

Background Frail lung transplant candidates are more likely to be delisted or die without receiving a transplant. Further knowledge of what frailty represents in this population will assist in developing interventions to prevent frailty from developing. We set out to determine whether frail lung transplant candidates have reduced exercise capacity independent of disease severity and diagnosis. Methods Sixty-eight adult lung transplant candidates underwent cardiopulmonary exercise testing (CPET) and a frailty assessment (Fried's Frailty Phenotype (FFP)). Primary outcomes were peak workload and peak aerobic capacity ( V ˙ O 2 ). We used linear regression to adjust for age, gender, diagnosis, and lung allocation score (LAS). Results The mean ± SD age was 57 ± 11 years, 51% were women, 57% had interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had cystic fibrosis, and the mean LAS was 40.2 (range 19.2–94.5). In adjusted models, peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V ˙ O 2 decreased by 1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V ˙ O 2 was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to non-frail participants. Frailty accounted for 16% of the variance (R2) of watts and 19% of the variance of V ˙ O 2 in adjusted models. Conclusion Frailty contributes to reduced exercise capacity among lung transplant candidates independent of disease severity.

Aim To collect information about how people with acne make day-to-day decisions concerning the effectiveness of their treatment. Methods Between May and August 2013, an optional question was embedded in the James Lind Alliance Acne Priority Setting Partnership's online survey to collect treatment uncertainties. The question asked people with acne to ‘Tell us in your own words how you decide if your treatment has been effective’. Results A total of 742 respondents specified at least one outcome or means of assessing change (outcome measure). Fewer spots was the most commonly cited outcome, identified by 272 respondents (36.7%). Other frequently mentioned outcomes were, in descending order: less redness (19.4%), reduction in spot size (12.1%) and less pain/discomfort (11.4%). Signs were much more commonly used than symptoms and surrogate outcomes such as changes in aspects of life quality were infrequently mentioned. Visual inspection of the skin was the most widely adopted outcome measure (16.3%). Conclusions Although the most frequently used methods map well onto the outcome measures adopted in the majority of acne trials, namely physician-assessed changes in lesion counts and global acne severity, people with acne often take into account several factors that cannot be assessed by a third party at a single point in time. The minimal use of changes in psychosocial wellbeing and mood may reflect that these are regarded as secondary consequences of improvements in appearance. The robustness of these findings now requires independent evaluation. If confirmed, they could form the basis of a new patient-reported outcome measure. This article is protected by copyright. All rights reserved

Purpose: To assess patient satisfaction and patient-related outcomes across the domains of appearance, cleansibility, and costs; the perceived value and worth when single implant crowns (SICs) had been in situ up to 14 years; whether satisfaction differed between patients; and whether certain characteristics might affect the questionnaire response rate. Materials and Methods: Patients treated at a private prosthodontic practice between 2001 and 2014 (n = 207) who received a SIC (n = 256) were prospectively included. A previously validated patient satisfaction questionnaire (PSQ) exploring patient-centered outcomes was mailed to participants. Demographic (sex, age) and treatment data (number of SICs, time in situ, failure experience, complication experience) were collected. Visual analog scale (VAS) responses were converted to percentages. Differences between respondents and nonrespondents, differences in satisfaction between prosthesis placement and survey date, and differences with respect to demographic and treatment data were assessed. Averages were medians bounded by interquartile ranges. Statistical significance was set at P =.05. Results: Respondents (n = 128, 61.8%) and nonrespondents (n = 79, 38.2%) had similar demographic and treatment characteristics. Prostheses had been in situ for up to 14 years (median, 5 years; interquartile range [IQR], 24 to 96 months). Participants reported that treatment met their expectations (median, 93%; IQR, 85% to 100%); they reported high satisfaction with tooth color, tooth contour, peri-implant mucosa, appearance overall, and ease of cleaning (medians ranging from 90.5% to 95%, IQR ranging from 80% to 100%) and medium satisfaction with costs when prostheses were placed (median, 50%; IQR, 29% to 80%). Satisfaction with tooth contour, peri-implant tissues, overall appearance, and costs significantly improved over time (96%, 92.5%, 91.7%, and 75%, respectively; P

Background The purpose of this work was to determine if parameters assessed during Cardiopulmonary Exercise Testing (CPET) while using supplemental oxygen can independently predict one-year transplant-free survival in patients with Interstitial Lung Disease (ILD) referred for lung transplant evaluation. Methods We performed a chart review of patients with ILD who completed CPET with 30% FiO 2 and gathered spirometry, pulmonary hemodynamic, six-minute walk, and CPET data. The primary end-point was death or lung transplantation within one-year of CPET. Results The final data set included 192 patients. 79 patients died/underwent transplant, 113 survived transplant-free. Multivariable Cox regression revealed peak workload % predicted, nadir CPET SpO 2 , and FVC% predicted as independent predictors of one-year transplant-free survival. Of the independent predictors of survival, receiver operating characteristics analysis revealed peak workload %predicted cutoff of 35% to be highly discriminatory, more so than nadir CPET SpO 2 or FVC % predicted in identifying patients at risk for one-year mortality or transplant (peak workload % predicted 2 Conclusion Peak workload % predicted, nadir CPET SpO 2 , and FVC% predicted in ILD patients referred for lung transplant evaluation are independently predictive of one-year mortality or need for transplant.

Progressive macular hypomelanosis (PMH) is a skin condition that normally causes symmetrically distributed hypopigmented macules on the front and back of the trunk, but rarely the face. To date, the pathophysiology of the condition is not well understood, but a role for the anaerobic skin bacterium Cutibacterium (previously Propionibacterium) acnes in the development of the disease has been proposed due to its sole presence within lesional, but not normal peri-lesional, skin. The success of antimicrobials in the treatment of PMH also provides circumstantial evidence that this association may be causal, although this is still to be proven. More recent culture and metagenomic typing studies indicate that strains of C. acnes subsp. elongatum (type III) may be important in the aetiology of the condition, which would help to explain why PMH does not normally affect the face since such strains are rarely present there, and why no association between this condition and acne vulgaris is found; acne appears to primarily involve type IA1 strains from C. acnes subsp. acnes (type I). In this review, we summarize current knowledge on the relationship between C. acnes and PMH, and re-examine previous challenges to the view that the bacterium plays a role in the condition against the backdrop of newly emerged data.

Cutaneous glands in humans include holocrine or sebaceous glands and merocrine or sweat glands. Merocrine glands are subdivided into apocrine, eccrine, and apoeccrine glands. Disorders of each of these cutaneous glands have been associated with disease. Apocrine glands in adults are found predominantly in the axillae and anogenital regions, with a few located in the ear canal (ceruminous glands) and eyelids (Moll’s glands). Disorders associated with apocrine glands include hidradenitis suppurativa, Fox–Fordyce disease, bromhidrosis, trimethylaminuria, and chromhidrosis. Eccrine glands are the sweat-producing glands of the skin. Many drugs and systemic diseases can influence the degree of sweating, such as thyroid disease, infection, carcinoid, and cholinergic drugs. In cystic fibrosis, the concentration of sodium chloride in sweat is increased. Meanwhile, acne is a common inflammatory skin disease often associated with significant psychosocial morbidity.

Background Acne can adversely impact those affected in multiple dimensions. The purpose of this study was to determine the most prominent impacts identified by acne patients and by clinicians. Methods Independent Delphi surveys for acne patients and clinicians were conducted to achieve consensus regarding acne impacts within each group. Acne patients were recruited from outpatient clinics of authors (AL, JT, and DT). The first phase involved qualitative responses, where emergent themes were identified and used to generate items for 2 subsequent phases. Results The qualitative phase generated 64 items in 3 themes: psychological, sociological, and treatment related. These items were independently ranked in importance by patients and by clinicians. Consensus for importance was achieved for 34 items by patients and 43 by clinicians. Patient-identified highest ranked items were being self-conscious, feeling unattractive, feeling uncomfortable in own skin, unattractive to others, would not want pictures taken, envious of people with clear skin, and time/effort spent concealing scarring; while clinicians identified feeling unattractive. Conclusions We identify acne impacts within psychological, sociological, and treatment-related domains by acne patients and clinicians. Further, we establish discrepancies between patients and clinicians regarding the impact of acne. This provides evidence for the importance of establishing patient-reported outcomes.

Unidirectional cytoplasmic incompatibility (CI) results in a postfertilization incompatibility between Wolbachia-infected males and uninfected females. CI contributes to reproductive isolation between closely related species and is used in worldwide vector control programs to drastically lower arboviral vector population sizes or to replace populations that transmit arboviruses with those resistant to transmission. Despite decades of research on the factors that influence CI, penetrance is often variable under controlled laboratory conditions in various arthropods, suggesting that additional variables influence CI strength. Here, we demonstrate that paternal D. melanogaster grandmother age influences the strength of CI induced by their sons. Older D. melanogaster females have higher Wolbachia densities and produce offspring with higher Wolbachia densities that associate with stronger CI. This work reveals a multigenerational impact of age on CI and expands our understanding of host-Wolbachia interactions and the biology of CI induced by the Wolbachia strain infecting the most widely used arthropod model, D. melanogaster., Wolbachia are obligate intracellular bacteria that are globally distributed in half of all arthropod species. As the most abundant maternally inherited microbe in animals, Wolbachia manipulate host reproduction via reproductive parasitism strategies, including cytoplasmic incompatibility (CI). CI manifests as embryonic death when Wolbachia-modified sperm fertilize uninfected eggs but not maternally infected eggs. Thus, CI can provide a relative fitness advantage to Wolbachia-infected females and drive the infection through a population. In the genetic model Drosophila melanogaster, the Wolbachia strain wMel induces variable CI, making mechanistic studies in D. melanogaster cumbersome. Here, we demonstrate that sons of older paternal D. melanogaster grandmothers induce stronger CI than sons of younger paternal grandmothers, and we term this relationship the “paternal grandmother age effect” (PGAE). Moreover, the embryos and adult sons of older D. melanogaster grandmothers have higher Wolbachia densities, correlating with their ability to induce stronger CI. In addition, we report that Wolbachia density positively correlates with female age and decreases after mating, suggesting that females transmit Wolbachia loads that are proportional to their own titers. These findings reveal a transgenerational impact of age on wMel-induced CI, elucidate Wolbachia density dynamics in D. melanogaster, and provide a methodological advance to studies aimed at understanding wMel-induced CI in the D. melanogaster model.

OBJECTIVE: Elevated anxiety and breast cancer worry can impede mammographic screening and early breast cancer detection. Genetic advances and risk models make personalized breast cancer risk assessment and communication feasible, but it is unknown whether such communication of risk affects anxiety and disease-specific worry. We studied the effect of a personalized breast cancer screening intervention on risk perception, anxiety and breast cancer worry. METHODS: Women with a normal mammogram but elevated risk for breast cancfer (N=122) enrolled in the Athena Breast Health risk communication program were surveyed before and after receiving a letter conveying their breast cancer risk and a Breast Health Genetic Counselor consultation. We compared breast cancer risk estimation, anxiety and breast cancer worry before and after risk communication, and evaluated the relationship of anxiety and breast cancer worry to risk estimation accuracy. RESULTS: Women substantially overestimated their lifetime breast cancer risk, and risk communication somewhat mitigated this overestimation (49% pre-intervention, 42% post-intervention, 13% Gail model risk estimate, p

Objective Evaluate Hexoskin performance on a stationary bike against "gold standard" laboratory equipment and develop adjustment models for future use in field settings. Methods Compared respiratory rate (RR), tidal volume (VT), minute ventilation (VE), and heart rate (HR) measured by the Hexoskin shirt to simultaneous spirometry and full 12-lead electrocardiogram during a laboratory based incremental exercise test on a stationary bicycle. Results Data from 17 participants demonstrated Hexoskin VT and VE had the best agreement in the submaximal exercise level (discrepancies less than or equal to 5.3%) with larger discrepancies observed at rest (less than or equal to 15.3%) and at maximal exercise level (less than or equal to 11.7%). The discrepancies for HR and RR were lower at all levels (less than 10%). Adjusting for sex and body weight allowed for a single VE algorithm across the entire range of effort (r = 0.89). Conclusion These discrepancies are acceptable for field use in comparison to the ranges typical of bicycle commuting.

The genus Wolbachia is an archetype of maternally inherited intracellular bacteria that infect the germline of numerous invertebrate species worldwide. They can selfishly alter arthropod sex ratios and reproductive strategies to increase the proportion of the infected matriline in the population. The most common reproductive manipulation is cytoplasmic incompatibility, which results in embryonic lethality in crosses between infected males and uninfected females. Females infected with the same Wolbachia strain rescue this lethality. Despite more than 40 years of research and relevance to symbiont-induced speciation, as well as control of arbovirus vectors and agricultural pests, the bacterial genes underlying cytoplasmic incompatibility remain unknown. Here we use comparative and transgenic approaches to demonstrate that two differentially transcribed, co-diverging genes in the eukaryotic association module of prophage WO from Wolbachia strain wMel recapitulate and enhance cytoplasmic incompatibility. Dual expression in transgenic, uninfected males of Drosophila melanogaster crossed to uninfected females causes embryonic lethality. Each gene additively augments embryonic lethality in crosses between infected males and uninfected females. Lethality associates with embryonic defects that parallel those of wild-type cytoplasmic incompatibility and is notably rescued by wMel-infected embryos in all cases. The discovery of cytoplasmic incompatibility factor genes cifA and cifB pioneers genetic studies of prophage WO-induced reproductive manipulations and informs the continuing use of Wolbachia to control dengue and Zika virus transmission to humans.

BACKGROUND: Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. METHODS: We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (

Background Effective management of acne vulgaris in primary care involves support (usually provided over a number of consultations) and prescription of effective treatments. However, consulting and prescribing patterns for acne in primary care are not well described. Objectives To describe the rate of primary-care consultations and follow-up consultations; prescribing patterns, including overall use of acne-related medications (ARMs); and initial and follow-up prescription for acne vulgaris in the U.K. Methods U.K. primary-care acne consultations and prescriptions for ARMs were identified in the Clinical Practice Research Datalink. Annual consultation rates (between 2004 and 2013) by age and sex, new consultations and consultations in the subsequent year were calculated, along with prescribing trends – during a new consultation and over the subsequent 90 days and year – using the number of registered patients as the denominator. Results Two-thirds (66.1%) of patients who had a new acne consultation had no further acne consultations in the subsequent year. Overall 26.7%, 24.9%, and 23.6% and 2.8% of patients were prescribed no ARM, an oral antibiotic, a topical antibiotic or an oral plus topical antibiotic, respectively, during a new acne consultation. In total 60.1% and 38.6% of patients prescribed an ARM received no further ARM prescriptions in the following 90 days and 1 year, respectively, despite most prescriptions being for 2 months or less. Prescribing rates for lymecycline and topical combined clindamycin and benzoyl peroxide increased substantially between 2004 and 2013. There were no important changes in consultation rates between 2004 and 2013. Conclusions These data suggest that patients with acne are receiving a suboptimal initial choice of ARMs, longitudinal care and prescribing.

INTRODUCTION In this study we investigated non-invasive, effort-independent measurement of ventilatory mechanics in patients with amyotrophic lateral sclerosis (ALS). METHODS Ventilatory mechanics were measured by optoelectronic plethysmography (OEP) in ALS patients and matched controls. Analysis determined whether OEP measurements correlated with standard clinical measures. RESULTS ALS patients (N = 18) had lower forced vital capacity percent predicted (55.2 ± 22.0 L) compared with controls (N = 15; 104.7 ± 16.2 L) and higher ventilatory inefficiency (49.2 ± 9.0 vs. 40.0 ± 3.5, respectively; P < 0.001 for both measures). Lower tidal volumes within the diaphragm area correlated with the dyspnea subscore calculated from the ALS Functional Rating Scale-revised (P = 0.031), and paradoxical movement of the ribcage compared with the abdominal compartment was seen in the most severe cases. CONCLUSIONS Evaluation of ventilatory mechanics in mild to severe ALS reveals dysfunction that is not readily detected by standard testing and ALS functional severity assessment measures. Muscle Nerve 54: 270-276, 2016.

Introduction Atrophic scarring occurs throughout the course of inflammatory acne and across the spectrum of severity. This study evaluates perceptions of the general population toward individuals with clear skin and acne scars. Methods An online survey administered in the USA, UK, Japan, Germany, France and Brazil to respondents 18 years and over presented three facial pictures of clear skin or digitally superimposed acne scars (but no active acne lesions) in a random fashion. At least one clear and one scar picture were presented to each participant. Results Among the 4618 responders, 33% themselves had facial acne scars. The skin was the first thing noticed about the face by 41% when viewing pictures with scars vs 8% viewing clear skin (p